2526 Vol. 5, 2526 –2531, September 1999
Clinical Cancer Research
Gains of 1q21– q22 and 13q12– q14 Are Potential Indicators for
Resistance to Cisplatin-based Chemotherapy in Ovarian
Cancer Patients1
Kazuya Kudoh,2 Masashi Takano,
Tomoyuki Koshikawa, Misako Hirai,
Sadao Yoshida, Yoshinori Mano,
Kenji Yamamoto, Kenji Ishii, Tsunekazu Kita,
Yoshihiro Kikuchi, Ichiro Nagata,
Masanao Miwa, and Kazuhiko Uchida
Department of Obstetrics and Gynecology, National Defense Medical
College, Tokorozawa, Saitama 359-8513, [K. K., M. T., Y. M., K. Y.,
K. I., T. Ki., Y. K., I. N.], and Department of Biochemistry and
Molecular Oncology, Institute of Medical Sciences, University of
Tsukuba, Ibaraki 305-8575 [T. Ko., M. H., S. Y., M. M., K. U.],
Japan
ABSTRACT
The mechanism of drug resistance in ovarian cancer is
multifactorial, and accumulation of multiple genetic changes
may lead to the drug-resistant phenotype. In our attempt to
find characteristic genetic changes in drug-resistant tumors,
we screened the whole genome for gene aberrations in 28
primary ovarian cancers using the comparative genomic
hybridization method. These cancers included 14 tumors
from patients who did not respond to cisplatin-based combination chemotherapy and 14 tumors from patients who
had complete response to the chemotherapy. We found gains
in chromosomal regions 1q21– q22 and 13q12– q14 to be
related to the drug-resistant phenotype in ovarian cancer
patients. Several genes encoding transcription factors, oncogenes, cell cycle regulators, and regulators of the apoptotic
pathway are located on these regions of the chromosomes,
and these genes are potential modulators for toxic insults in
cancer cells. This is the first report that shows the relationship between certain genomic aberrations and clinical resistance to cisplatin-based chemotherapy in ovarian cancer
patients based on the comparative genomic hybridization
analysis. Present findings suggest that these chromosomal
gains may be potential indicators for prediction of resistance
Received 1/6/99; revised 5/4/99; accepted 5/4/99.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
1
Supported in part by Grants-in-Aid for Cancer Research from the
Ministry of Education, Sciences, Sports and Culture of Japan and from
the second-term Comprehensive 10-Year Strategy for Cancer Control
and Cancer Research from the Ministry of Health and Welfare of Japan.
2
To whom requests for reprints should be addressed, at Department of
Obstetrics and Gynecology, National Defense Medical College, 3-2
Namiki, Tokorozawa, Saitama 359-8513, Japan. Phone: 81-42-9951687; Fax: 81-42-996-5213; E-mail: [email protected].
in ovarian cancer patients before cisplatin-based chemotherapy.
INTRODUCTION
Ovarian cancer is the leading cause of death from gynecological cancer in the United States and Japan (1). Initially, cisplatin-based combination chemotherapy is associated with a 40 – 60% clinical response rate. However, the
overall 5-year survival rate for advanced ovarian cancer
patients is still around 20% (2). This low survival rate is due
to the fact that some primary tumors and most recurrent
tumors develop drug resistance that leads to treatment failure
(3). Thus, overcoming drug resistance is the key to successful
treatment of ovarian cancer.
Mechanisms of cisplatin resistance in human cancer cells
have been examined extensively in vitro. Decreased drug accumulation and activated detoxification pathways, such as increased cellular levels of glutathiones, g-glutamylcysteine synthetase (3), glutathione S-transferase p, or metallothioneins,
may be associated with cisplatin resistance (4, 5). Recent studies
on normal cell cycle and apoptotic regulatory pathways provided insights into the involvement of their regulators in the
cellular response to DNA-damaging agents, showing a possible
role for the cisplatin-resistant phenotype in human cancer (6 –9).
Because DNA repair through transcriptional induction of
GADD45 (10), ERCC1 and ERCC3 (11), or transcription factor
IIH-associated nucleotide excision repair (12) occurs after DNA
damage, the role of these genes in the drug-resistant phenotype
has been reported. Possible regulation of DNA repair by a
mutated cAMP-dependent protein kinase regulatory subunit in
cisplatin-resistant Chinese hamster ovary cells has also been
observed (13). In addition, transcription factor nuclear factor kB
(5, 14), metastasis suppressor gene nm-23 (15), mismatch repair
genes hMLH2 and hMSH1 (16), cell matrix protease cathepsin D
(17), the multidrug resistance P-glycoprotein and its relatives
multidrug resistance-associated protein and lung resistanceassociated protein (18), and growth factor receptors epidermal
growth factor receptor or HER-2/neu (19) have been evaluated
for their role in cisplatin resistance in various human cancer
cells.
In clinical resistance to cisplatin-based chemotherapy,
the status of these genes has been evaluated as a potential
marker for the drug-resistant phenotype and prognosis (20 –
22). Nevertheless, the underlying mechanisms and pathways
that lead to clinical drug resistance seem complex and are not
well understood. In view of tumor heterogeneity and the large
number of genetic changes accumulated through tumorigenesis (23), it is necessary to investigate all of the genetic
changes that yield the drug-resistant phenotype by a wholegenome approach.
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Clinical Cancer Research 2527
CGH,3 developed by Kallioniemi et al. (24, 25), is one of
the most powerful cytogenetic tools for the analysis of structural
genetic abnormalities in the entire genome in a single experiment. Several novel aberration sites in human cancers have been
found by CGH studies (26), but to our knowledge, no attempt at
showing a correlation between CGH profiles and drug-resistant
phenotypes in ovarian cancer patients has been reported. Our
purpose in this study is to identify patterns of genetic changes
that would predict resistance to chemotherapy in patients with
ovarian cancer.
Table 1 Clinical characteristics of 28 primary ovarian cancers
Case no.
Pathology
Stagea
Responseb
108
133
141
159
160
111
128
161
163
150
104
148
171
173
Serous
Serous
Serous
Serous
Serous
Serous
Mucinous
Mucinous
Endometrioid
Endometrioid
Endometrioid
Endometrioid
Clear cell
Clear cell
IIIC
IIIC
IIIC
IIIC
IIIC
IV
IIC
IIIA
IIC
IIIB
IIIC
IIIC
IIC
IIC
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
112
164
166
172
119
158
145
134
101
165
109
132
152
167
Serous
Serous
Serous
Serous
Serous
Mucinous
Mucinous
Endometrioid
Clear cell
Clear cell
Clear cell
Clear cell
Clear cell
Clear cell
IIIC
IIIC
IIIC
IIIC
IV
IIIC
IV
IC
IV
IIIB
IIIC
IIIC
IIIC
IIIC
PD
PD
PD
PD
PD
PD
PD
PD
PD
PD
PD
PD
PD
PD
MATERIALS AND METHODS
Patients, Chemotherapy, and Response Evaluation.
Of 71 patients with primary epithelial ovarian cancer treated at
the National Defense Medical College Hospital (Saitama, Japan)
between 1993 and 1997, the following patients were selected:
(a) patients who received no chemotherapy prior to any surgical
therapy; (b) patients who harbored any residual tumors after
initial debulking surgery; and (c) patients treated with six
courses of cisplatin-based combination chemotherapy (described below) after the initial surgery. The subjects were then
grouped into the following four categories according to their
response to chemotherapy: (a) CR; (b) partial response; (c) no
change; and (d) PD (3). Only patients in the CR (n 5 14) and PD
(n 5 14) groups were included in this study. Our chemotherapy
regimen for primary epithelial ovarian cancer was as follows: a
drip infusion of 50 mg/m2 cisplatin for 3 h accompanied by an
i.v. injection of 50 mg/m2 doxorubicin and 500 mg/m2 cyclophosphamide was given every 4 weeks for six courses (3).
Histological diagnosis was confirmed by microscopic examination of H&E-stained sections according to the WHO criteria.
Clinical stages were determined according to the International
Federation of Gynecology and Obstetrics (FIGO) system.
DNA Extraction. High molecular weight genomic
DNAs from primary tumors were isolated by proteinase K
digestion, phenol-chloroform extraction, and ethanol precipitation, as described previously (27). All samples were examined
by 1% agarose gel electrophoresis for conservation of high
molecular weight.
CGH. CGH was performed by indirect labeling methods
(24) with slight modifications. Briefly, tumor DNA and reference DNA were labeled by nick translation with biotin-16dUTP (Boehringer Mannheim, Manheim, Germany) and digoxigenin-11-dUTP (Boehringer Mannheim), respectively. Before
hybridization, the metaphase preparation from normal lymphocytes (Vysis, Downers Grove, IL; FML, Tokyo Japan) was
denatured at 73°C for 5 min in 70% formamide and 23 SSC
[13 SSC 5 0.15 M NaCl-0.015 M sodium citrate (pH 7.0)] and
dehydrated by sequential immersion in 70% ethanol at 220°C,
85% ethanol at RT, and 100% ethanol at RT. A total of 900 ng
of labeled tumor and reference DNAs with 10 mg of human
Cot-1 DNA (Life Technologies, Inc., Gaithersburg, MD) in 10
3
The abbreviations used are: CGH, comparative genomic hybridization;
CR, complete response; PD, progressive disease; RT, room temperature;
PNM, 0.1 M Na2HPO4, 0.1% NP40, and 1% skim milk.
a
FIGO clinical stage.
Response to cisplatin-based chemotherapy, represented by either
CR or PD, according to the criteria proposed by the Japanese Association for Cancer Treatment.
b
ml of hybridization buffer (50% formamide, 10% dextran sulfate, and 23 SSC) were denatured for 5 min at 73°C and applied
onto metaphase cells on slides. Hybridization was performed at
37°C for about 60 h in a moisturized chamber. Posthybridization
washes were performed as follows: (a) three times in 50%
formamide/23 SSC; (b) twice in 23 SSC; and (c) once in 0.13
SSC at 45°C for 10 min each. Staining was performed as
described below. After blocking in 1% BSA/43 SSC for 5 min,
slides were incubated with 1% BSA/43 SSC containing 5
mg/ml FITC-conjugated avidin (Vector Laboratories) for 30 min
at RT and washed sequentially with 43 SSC, 0.1% Triton
X-100/43 SSC, and 43 SSC at RT for 10 min each. After
blocking in PNM, slides were incubated with 2 mg/ml rhodamine-conjugated antidigoxgenin antibody (Boehringer Mannheim) and 5 mg/ml biotinylated antiavidin antibody (Vector
Laboratories) in PNM for 45 min at RT. Slides were washed
four times with 0.1 M Na2HPO4 and 0.1% NP40 for 5 min at RT
and then immersed in PNM for 5 min, followed by incubation in
PNM containing 5 mg/ml FITC-conjugated avidin for 30 min at
RT. The slides were washed twice with 0.1 M Na2HPO4 and
0.1% NP40 for 5 min and washed twice with distilled water for
5 min. Chromosomes were counterstained with 49,6-diamidino2-phenylindole (Molecular Probes, Inc., Eugene, OR).
Digital Image Analysis. Metaphase images were analyzed by a cooled charge-coupled device camera (Applied Imaging, Santa Clara, CA) attached to a fluorescence microscope
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2528 1q21 and 13q12 Gains in Clinically Resistant Ovarian Cancer
Fig. 1 Chromosomal aberrations of primary epithelial ovarian cancers. The aberrations in
the CR group (A) and the PD
group (B) are shown separately.
Lines on the right and left sides,
gains and losses of DNA copy
number, respectively. Each line
represents an alteration of one
tumor.
(Leica, Wetzlar, Germany). Three-color images (green, labeled
tumor DNA; red, labeled reference DNA; and blue, counterstaining) were captured. Digital images were processed for
quantitation of fluorescence intensity with Cytovision software
(Applied Imaging). The green:red fluorescence ratio along individual chromosomes was calculated. The green:red ratios
from several metaphases were averaged and plotted along the
chromosomes. Reliability was assessed with 95% confidence
intervals. Ratios higher than 1.25 were defined as chromosomal
gains, and ratios below 0.75 were defined as chromosomal
losses, respectively (24). The telomeric and heterochromatic
regions were excluded from CGH analysis (24).
Statistical Analysis. Fisher’s exact test was used to evaluate the relationship between chromosomal status and clinical or
biological features.
RESULTS
In this study, we analyzed the patterns of genetic aberration
in 14 PD group tumors and 14 CR group tumors from patients
with primary epithelial ovarian cancer (Table 1). CR group
cases consist of six serous, two mucinous, four endometrioid,
and two clear cell adenocarcinomas. Ten of the 14 CR cases
were stage III–IV. PD group cases consist of five serous, two
mucinous, one endometrioid, and six clear cell adenocarcinomas. Thirteen of the 14 PD cases were stage III–IV. Fig. 1
shows schematic representations of all chromosomal aberrations
found in CR group patients (Fig. 1A) and PD group patients
(Fig. 1B). Each tumor from CR and PD group patients harbored
more than three regions of genetic aberration, and the average
number of regions with genetic changes in CR and PD group
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Clinical Cancer Research 2529
Table 2 Association of 1q21– q22 and 13q12– q14 gains with PD in
primary ovarian cancers
Chromosome
regiona
CR (%)b
(n 5 14)
PD (%)b
(n 5 14)
Total (%)
(n 5 28)
Pc
11q21–q22
13q13
13q28
18q24
19q34
112p13
113q12–q14
213q31
117q25
120q13.1
2 (14)
4 (29)
8 (57)
6 (43)
1 (7)
0 (0)
0 (0)
1 (7)
5 (36)
4 (29)
9 (64)
7 (50)
7 (50)
7 (50)
5 (36)
4 (29)
5 (36)
5 (36)
6 (43)
9 (64)
11 (39)
11 (39)
13 (46)
13 (46)
6 (21)
4 (14)
5 (18)
6 (21)
11 (39)
13 (46)
0.0183
NS
NS
NS
NS
NS
0.0407
NS
NS
NS
a
Regions of chromosomal gains and losses observed in 28 primary
ovarian cancers. In the first column, 1 and 2 represent gain and loss,
respectively.
b
Response to cisplatin-based chemotherapy, represented by either
CR or PD, according to the criteria proposed by the Japanese Association for Cancer Treatment. Values in parentheses are the percentage of
the total number of CR or PD tumors.
c
The association of each gene aberration with PD in primary
ovarian cancers was estimated by Fisher’s exact test and represented
as P.
tumors was 11.6 6 9.2 and 15.9 6 8.6, respectively. The
number of chromosomes involved in genetic changes in CR and
PD group tumors was 9.1 6 6.0 and 11.9 6 5.3, respectively.
As shown in Table 2, frequent alterations observed in
primary ovarian cancer were gains at 1q21– q22 (11 of 28
patients, 39%), 3q13 (11 of 28 patients, 39%), 3q28 (13 of 28
patients, 46%), 8q24 (13 of 28 patients, 46%), 17q25 (11 of 28
patients, 39%), and 20q13.1 (13 of 28 patients, 46%). In comparison to the genetic changes in CR group tumors, more frequent gains at 1q21– q22 (9 of 14 patients, 64%), 9q34 (5 of 14
patients, 36%), 12p13 (4 of 14 patients, 29%), 13q12– q14 (5 of
14 patients, 36%), and 20q13.1 (9 of 14 patients, 64%) and loss
at 13q31 (5 of 14 patients, 36%) were observed in PD group
tumors. In the CR group tumors, gains at 12p13 or 13q12– q14
were not observed, and gains at 1q21– q22 (2 of 14 patients,
14%) and 9q34 (1 of 14 patients, 7%) and loss at 13q31 (1 of 14
patients, 7%) were observed in only a small number of cases
(Table 2).
We performed a statistical analysis for the existence of a
correlation between the abundance of certain gene aberrations
and the clinical drug-resistant phenotype. As a consequence,
only gains at 1q21– q22 (P 5 0.0183) and 13q12– q14 (P 5
0.0407) were observed in significantly high abundance in PD
group tumors, compared to those of CR group tumors (Table 2).
Other changes, including gains at 3q13, 3q28, 8q24, 9q34,
12p13, 17q25, and 20q13.1 and loss at 13q31, did not show any
significant difference in abundance between the PD and CR
group tumors. Frequent aberrations on chromosomes 1q and 13q
in PD group tumors are shown schematically in Fig. 2, compared to those of CR group tumors.
DISCUSSION
In this study, we examined the associations between patterns of genetic alterations and response to chemotherapy, which
is one of the most important factors for achieving remission in
Fig. 2 Frequent chromosomal aberrations on chromosomes 1q and 13q
in PD group tumors (right) of primary epithelial ovarian cancers, as
compared to the CR group tumors (left). The frequency of each aberration is designated in Table 2.
advanced or recurrent ovarian cancer (1–3). Our data show that
drug-resistant tumors harbor a larger number of chromosomal
regions with genetic abnormalities. This is because the majority
of ovarian cancers appear to be sporadic and have complex
accumulation of multiple genetic changes, which may contribute
to the development and progression of cancer and, consequently, provoke the drug-resistant phenotype (23). In a previous study, Wasenius et al. (28) reported that gains in chromosomes 2q, 4, 6q and 8q or losses in chromosomes 2p, 7p, 11p,
13, and X were the genetic imbalances responsible for cisplatin
resistance in ovarian cancer cell lines. However, no characteristic CGH patterns in clinically resistant tumors have been
reported to date.
Our data show a significantly higher ratio of genetic
changes characterized by 1q21– q22 and 13q12– q14 gains in
cisplatin-resistant tumors than in cisplatin-sensitive tumors (Table 2). Abnormalities in 1q21, including amplifications, rearrangements, and translocations, have been reported in a number
of human solid tumors and hematological malignancies (29, 30).
Genetic abnormality is also associated with poor chemotherapeutic response in B-cell lymphoma (31). Many candidate genes
contributing to the drug-resistant phenotype are located on
1q21– q22, including BCL-2-related myeloid leukemia sequence
(MCL-1), cathepsins (CTSS and CTSK), the polymorphic mucinous tumor-associated gene (MUC-1), Src homology 2 domains
containing transforming protein 1 (SHC-1), the transcription
factor-like 1 (YL-1 or TCFL-1), and the papillary renal cell
carcinoma gene (PRCC). Several reports showed that up-regulation of MCL-1 expression, along with GADD45 and BAX, was
caused by DNA-damaging agents in cells sensitive to apoptosis,
thus suggesting a possible role for these genes in drug resistance
(29). The MUC-1 gene was reported to be frequently amplified
and expressed in breast cancer, indicating a potential role in the
carcinogenesis of breast tumors (30). The role of these genes
and their abnormalities in the drug-resistant phenotype in ovarian cancer remain to be examined.
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2530 1q21 and 13q12 Gains in Clinically Resistant Ovarian Cancer
Gain in 13q12– q14 is also interesting because it is observed only in drug-resistant tumors (Table 2). This region
contains the retinoblastoma 1 gene (RB1) and the breast cancer
2 gene (BRCA2), as well as several candidate genes, including
thioredoxin-dependent peroxidase reductase (TDPX1) and forkhead 1 in rhabdomyosarcoma (FKHR). The thioredoxin-dependent peroxide reductase encoded by TDPX1 modulates the activity of the thioredoxin system, which plays a major role in
removing reactive oxygen species and free radicals (32). This
system is also involved in the acquisition of drug resistance in
certain types of malignant tumors (32). The FKHR gene encodes
a transcription factor that fuses with the transcription activator
PAX3 and acts as an oncogene in rhabdomyosarcoma (33).
Overexpression of wild-type p53 in cells containing the PAXFKHR fusion protein shows sensitization to DNA-damaging
agents, suggesting a possible role of these gene products in the
drug-resistant phenotype (33).
Gains in 9q34, 12p13, and 20q13.1 and loss at 13q31 were
also observed more frequently in drug-resistant tumors. However, none of these abnormalities was statistically significant,
possibly due to the sample size.
Gains of chromosomal regions 3q and 8q are the most
commonly observed changes in ovarian cancer, as well as in
breast, prostate, and renal carcinomas (26, 34, 35). Iwabuchi et
al. (34) showed a high frequency of 3q26 amplification in
poorly differentiated ovarian cancer. A recent report shows a
frequent copy number increase of the telomerase gene (hTR)
located on chromosome 3q26 (36). A few reports show that
telomerase activity can be modulated by chemotherapy in human cancer (37), but no relationship between drug resistance
and telomerase activity has been shown. The commonly gained
loci 8q24 is known to harbor the C-MYC oncogene, which is
reported to be amplified in 30% of ovarian cancer (38). Amplification of 3q28 and 8q24 was present in 46% of the clinical
specimens, regardless of their response, suggesting that these
genetic imbalances are related to oncogenesis but not to the
drug-resistant phenotype in ovarian cancer.
With regard to previous studies of functional analysis on
drug-resistant tumors, the amplification of chromosomal regions
for MDM-2 on 12q14.3– q15, MYCN on 2p24.1, EGFR on
7p12.1–p12.3, PGY1 encoding P-glycoprotein on 7q21.1, and
GLCLC encoding g-glutamylcysteine synthetase on 6p12 or loss
of the regions for the TP53 gene on 17p13.1 and CDKN2A
encoding p16 on 9p21 are possible genetic changes in drugresistant ovarian tumors. In our study, however, these genetic
changes are not observed in the drug-resistant tumors. It is
possible that the expression of some of the genes is regulated at
the transcriptional or posttranscriptional level, but not by gene
amplification (5). Moreover, some of the changes may be too
small in size to be detected by CGH analysis because the
minimum detectable size is reported to be 5–10 Mb or more (24,
25).
Becuse CGH is a purely cytogenetic analytical method, the
result does not lead directly to gene isolation. However, those
regions that show frequent changes in drug-resistant tumors may
be exploited as indicators for predicting the drug-resistant phenotype for cisplatin-based chemotherapy in ovarian cancer patients. Recent development of cDNA microarray technology
may enable the analysis of whole expression of genes that may
contribute to the drug-resistant phenotype in human cancer
through its potential ability to approach functional genomics
(39, 40). Together with the data from the CGH analysis of
drug-resistant tumors in ovarian cancer patients, this information may offer significant insights into the dominant mechanisms that lead to the drug-resistant phenotype in these patients.
ACKNOWLEDGMENTS
We thank Khew-Voon Chin and Mary Ellen Cvijic for helpful
reading of and comments on the manuscript.
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Research.
Gains of 1q21−q22 and 13q12−q14 Are Potential Indicators for
Resistance to Cisplatin-based Chemotherapy in Ovarian
Cancer Patients
Kazuya Kudoh, Masashi Takano, Tomoyuki Koshikawa, et al.
Clin Cancer Res 1999;5:2526-2531.
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